Tuberculosis can affect any organ of the body and is manifested in several different forms, but the primary site of infection is the lung. Tuberculosis affecting the lungs is known as pulmonary tuberculosis. Pulmonary tuberculosis is the most predominantly occurring form of tuberculosis (Tuberculosis, 2005, 85, 227-234). The current chemotherapeutic regimen for treating pulmonary tuberculosis consists of co-administration of front-line antitubercular drugs (isoniazid, rifampicin, ethambutol, and/or pyrizinamide) for a period of four months followed by two months of treatment with isoniazid, rifampicin, and/or ethambutol, but depending upon the type of tuberculosis, the treatment can be further extended upto a period ranging from 9 months to 2 years. This current chemotherapeutic regimen is given in the form of once a day oral dosing, which is associated with poor plasma half-life (International Journal of Pharmaceutics, 2004, 276, 41-49) and a plethora of dose related adverse effects (Journal of Antimicrobial Chemotherapy, 2004 54, 761-766). These adverse effects are attributed to an undesirable biodistribution profile. Moreover, in respect of the orally administered drugs it has been observed that only a small fraction of the drug reaches the site of action i.e. the lungs and is cleared within hours (Tuberculosis, 2005, 85, 227-234). The above problems are associated with poor patient compliance and result in the development of multidrug resistant tuberculosis (MDRTB).
MDRTB is a form of tuberculosis that is resistant to at least two of the best antitubercular drugs, isoniazid and rifampicin (Multidrug resistant tuberculosis fact sheet, Center for Disease Control, 2008). MDRTB is treated with second line antitubercular drugs like fluoroquinolones, aminoglycosides like amikacin, kanamycin, capreomycin, para-aminosalicyclic acid and thioacetazone (Treatment of drug resistant tuberculosis, fact sheet, Center for Disease Control, 2007). The second line tuberculosis drugs are associated with dose related side effects, poor bioavailability in the lungs, which is detrimental for disease eradication.
Analogous to the problem of pulmonary tuberculosis, the problems of poor bioavailability of drugs and higher dose induced adverse effects are also encountered in the treatment of MRSA and MSSA pneumonias. Nosocomial pneumonias and ventilator-associated pneumonias resulting from MRSA are associated with high mortality rates (International Journal of Antimicrobial Agents, 2007, 30, 19-24), the reason for the aforesaid being inadequate treatment.
First line drugs that are used to treat MRSA pneumonia include vancomycin and linezolid. Vancomycin, the drug of choice for treating MRSA pneumonia, is associated with unsatisfactory pharmacokinetic profile in the lung tissue and has lung concentrations, which are just 20% of the plasma concentrations (Antimicrob. Agents Chemother., 1999, 37, 281-286). Moreover, long-term administration of vancomycin is associated with nephrotoxicity, which is a dose-limiting factor (Clin. Microbiol. Infect., 2006, 12, 92-95). Linezolid, which is accepted for therapy in MRSA pneumonia, exhibits good oral bioavailability (administered as 600 mg oral twice daily) but is associated with gastrointestinal adverse effects, thrombocytopenia, and reversible anemia (Clinical Infect. Dis., 2003, 37, 1609-1616). On rare occasions, administration of linezolid is also associated with optic and peripheral neuropathy (J. Antimivrob. Chemother., 2004, 53, 1114-1115).
Beta lactam agents (such as ampicillin and cepholosporins) are very effective against MSSA pneumonia as first line of therapy. Though vancomycin is considered as next line of therapy, it is not as effective as the beta lactam agents in infections caused by MSSA. Also vancomycin is excreted in the urine by glomerular filtration and is not metabolized. Lung tissue penetration of vancomycin is also relatively poor (US Respiratory Disease, 2006, 62-64). In summary, the therapy for MRSA/MSSA pneumonia has several drawbacks such as poor pulmonary bioavailability of drugs, drug dosage induced toxicity, etc.
To overcome the problems associated with the current standard treatment regimen and patient non-compliance, it is essential to develop a drug delivery system that directly reaches the site of action, has the potential to target the lung macrophages where mycobacteria reside and reduce drug associated systemic toxicity.